OTOLITH-SPECIFIC VESTIBULAR DYSFUNCTION IN THE LE-DOUB RAT: A NEW MODEL FOR VESTIBULAR RESEARCH

A spontaneous mutation has led to the establishment of the LEDOUB (Long-Evans Defective Otoconia Universitat de Barcelona) rat line, which serves as a genetically defined model of vestibular loss. This novel model is characterized by complete absence of otoconia with preserved semicircular canal structure. Lack of otoconia in the otolithic membrane of the utricle and saccule impedes vestibular functions such as detection of head position and linear acceleration. Otolith-specific vestibular loss has primarily been studied in genetic mouse models, relying on global balance and motor tests. In the rat however, established anti-gravity reflex tests provide robust objective and quantitative measures of vestibular dysfunction. Preliminary anti-gravity reflex assays of LEDOUB rats reveal delayed and incomplete air-righting responses but roughly normal tail-lift reflexes, aligning with the predicted loss of otolith-driven input while preserving canal-mediated functions. Immunohistochemical and ultrastructural analyses confirm intact hair-cell organization and macular structure but a complete absence of otoconia. Dose-response experiments with the ototoxic compound 3,3'-iminodipropanenitrile (IDPN) show similar susceptibility across genotypes, indicating that macular hair-cell activity does not modulate ototoxic susceptibility to hair-cell loss. These findings support the hypothesis that selective loss of otolithic function produces dissociable deficits in otolith-dependent reflexes while sparing canal-mediated function, offering a new avenue to functionally differentiate otolith and canal contributions to vestibular sensory processing. Funding: European Union under Grant Agreement No. 101120139.